populations exposed to radiation. There is some evidence indicative of lower lung
cancer risks at any particular level of smoking among Japanese smokers, compared to

U.S. smokers (see altached report).

= There is a larger body of literature on combined effects of smoking with other agents,
€.g., asbestos. This evidence was reviewed in the 2004 monograph of the Intemational
Agency for Research on Cancer (IARC 2004) with the general conclusion that

synergism between smoking and some other agents has been demonstrated for cancer.

Conciusions and Recommendations:

The materials provided demonstrate sensitivity of risk predictions to choice of underlying model
and to the data from which the models parameters are estimated. Model sensitivity is to be
anticipated and is an indication of the uncertainty in the general approach to estimating the
probability of causation. In this setting of model uncertainty and the impossibility of selecting
one model as “correct”, maintaining the two models seems warranted, particularly to assure that
the decision to provide compensation would tend to be inclusive rather than exclusive. 1 would
not weight the finding of the new analysis by Pierce et al. so heavily as to use only the NIH

model. My rationale for this view is given in my comments on the paper by Pierce et al.

For these reasons, I favor the retention of both models, with decision-making based on the higher
probability of causation. Consideration should be given to updating the NIOSH model using the

updated RERF data.



cancer relative risks, the temporal profile of smoking and its age-birth cohort

dependence complicate interpretation of models with time-dependent factors.

While extension of the follow-up interval by four years has added further cases, and
included coverage of a time period with a higher relative risk, the increment to the
total database in terms of follow-up time and number of cases must be modest. I
would thus be surprised if there was strong evidence supporting a departure from

earlier analytic findings.

attention to measurement crror in the assessment of smoking and the possibility of age

and birth-cohort dependent measurement error.

Pierce et al. recognize that the lung cancer model for smoking is limited, reflecting in
part data availability. Would inadequate model specification tend to bias assessment

of effect modification towards additivity?

1 have additional comments concerning the general approach of relying primarily on the data

from the atomic bomb survivors.

Others have commented on uncertainty in extrapolating risk models from the atomic
bomb survivors to other populations. For lung cancer, there is the particular concern

of the different pattern of smoking among Japanese males, compared to U.S.



JOHNS HOPKINS

Bloomberg School of Public Health

Department of Epidemialogy

615 N. Wolte Street » Suite W6041
Baltimore MD 21205-2170
410-955-3286 : Fax 410-614-0487

Oftice of the Chairman

February 22, 2005

Memorandum

TO: Russ Henshaw, M.S., Epidemiologist

| Ow HOA
FROM: Jondthan M. Samet, M.D., M.S., Professor and Chair
SUBJECT: Review of Lung Cancer Risk Models

Attached please find my review of the materials concerning the two models for lung cancer
prediction. I have also attached an invoice for my time in preparing this report.



Evaluation of Two Models for Projecting Lung Cancer Risk: NIOSH-IREP and NIH-IREP
Jonathan M. Samet, M.D., M.S.
Professor and Chair

Department of Epidemiology
Johns Hopkins Bloomberg Schoo! of Public Health

Background:

This report, prepared at the request of the National Institute for Occupational Safety and Health
(NIOSH), addresses two models used for projecting lung cancer risk, one prepared by NIOSH
and the other by the National Institutes for Health (NIH). Both modcls have their origins in work
initially carried out in the 1980s following a congressional request to the NIH to prepare tables of
estimated probabilities that cancers were caused by radiation. Over time, these models have
been modified as additional information became available and the conceptual basis for modeling
lung cancer risk evolved. For lung cancer, two bodies of epidemiological evidence have been
particularly critical: 1) the data from studies of the atomic bomb survivors; and 2) the data from
the studies of uranium and other underground miners exposed to radon. The former data have
been analyzed over time by investigators at the Radiation Effects Research Foundation (RERF)
as well as by the Biological Effects of Ionizing Radiation (BEIR) Committees of the National
Research Council. Similarly, the data from underground miners have been evaluated by the
individual investigators, by a pooling group convened by the National Cancer Institutes and by

the BEIR IV and BEIR VI Committees.

The NIOSH and NIH models have recently diverged, with a modification of the NIH model to
incorporate the most recent analysis of the atomic bomb survivor data. As demonstrated in an

assessment of the two models prepared by Apostoaei and Trabalka, the models give divergent



predictions for some scenarios of age at exposure, attained age, and smoking. The differences
reflect specifications of the underlying models, and also differences in the data used for model
estimation. As a reviewer, I have been asked to indicate which model, or models, should be used
in estimating probability of causation for compensation under the Energy Employees

Occupational Illness Compensation Program Act of 2000 (EEOICPA).

Comments:

In providing comments, I initially offer my evaluation of the most recent analysis of the atomic
bomb survivors data carried out by Pierce et al. and reported in Radiation Research in 1993.
This analysis included follow-up for the years 1950 — 1994 and was incorporated into the NIH-
TREP, while the NIOSH-IREP model is based only on follow-up from 1950 — 1990, With regard
to the new analysis by Pierce et al., | have the following comments pertinent to its use in NIH-

TREP:

* — Pierce ct al. note that the dataset has become more informative because of rising
relative risks for lung cancer in Japan, likely reflecting patterns of smoking. With
colleagues, I have recently prepared an extensive report on smoking and disease risks
in Japan. Tam attaching information concerning the smoking profile in Japan, which
supports the premise, albcit undocumented, of Pierce et al. Of note, a high proportion
of Japanese men were smoking following World War II, but the numbers of cigarettes
smoked did not reach the current pattern of approximately one pack per day until the

late 1960s and early 1970s. While Pierce et al. are correct in regard to rising lung